The trimethylsilyl xylyl (TIX) ether: A useful protecting group for alcohols

Article abstract of DOI:10.1016/j.tet.2004.11.023

A new protecting group for alcohols, the p-trimethylsilyl xylyl (TIX) group has been developed. The TIX group is used to protect various alcohols under acidic as well as basic conditions. The protected ethers thus formed had noteworthy chemoselectivity upon deprotection in the presence of other benzyl ethers and commonly used protecting groups. The stability of the TIX group towards various reagents has also been examined.

Full text of DOI:10.1016/j.tet.2004.11.023

Tetrahedron 61 (2005) 1289–1295
The trimethylsilyl xylyl (TIX) ether: a useful protecting group
for alcohols
Ch. Raji Reddy,a Amar G. Chittiboyina,a Rajashaker Kache,a Jae-Chul Jung,a
E. Blake Watkinsa and Mitchell A. Averya,b,
*
aDepartment of Medicinal Chemistry, School of Pharmacy, Center for Natural Products Research, University of Mississippi,
417, Faser Hall, PO Box 1848, University, MS 38677-1848, USA
bDepartment of Chemistry, University of Mississippi, 417, Faser Hall, PO Box 1848, University, MS 38677-1848, USA
Received 28 September 2004; revised 10 November 2004; accepted 10 November 2004
Available online 8 December 2004
Abstract—A new protecting group for alcohols, the p-trimethylsilyl xylyl (TIX) group has been developed. The TIX group is used to protect
various alcohols under acidic as well as basic conditions. The protected ethers thus formed had noteworthy chemoselectivity upon
deprotection in the presence of other benzyl ethers and commonly used protecting groups. The stability of the TIX group towards various
reagents has also been examined.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
can be cleaved easily, and are employed as temporary
protecting groups that can be removed conveniently at
earlier stages of the synthesis when more delicate
functionality is present.
Protection and deprotection are inevitable requirements of a
lengthy synthetic sequence leading to natural products, fine
chemical intermediates, or important industrial or pharma-
ceutical organic materials. Protecting groups exist for
various functional moieties and have their own pattern of
chemoselectivity during deprotection. In molecules with
multiple, discrete, simultaneous protections, a careful
strategy exists for specific removal and modification of
the exposed functionality. Thus, elaborately protected,
highly functional templates can serve as total synthetic
intermediates. In addition, such templates bound to solid
support can lead to diversity upon chemoselective deprotec-
tion of various functional groups with subsequent elabo-
ration of the liberated functional group. To date, a
remarkable variety of protecting groups have been reported
and their preparation, attachment and deprotection strat-
egies under a variety of conditions have been summarized
nicely.1
A number of esoterically substituted benzyl ethers have
been reported in the literature including methoxy, nitro,
halo, cyano, azido benzyl ethers, etc.1,2 Among these, the
p-methoxy benzyl (PMB) group has found frequent
application in natural product synthesis, and can be removed
oxidatively in a selective manner.3 However, the sensitivity
of this group to acid4 severely restricts its synthetic utility.
Recently, p-substituted benzyl ethers with acetoxy, SEM
and halo substituents have been reported.5 Although these
groups offer some advantages, the cleavage conditions are
incompatible with either base-sensitive or acid-sensitive
groups or functionalities. The development of a benzyl
protecting group that is stable to both acidic and basic
conditions is certainly a useful addition to the existing
substituted benzyl ethers.
Among hydroxyl protecting groups, benzyl ethers are highly
robust and are often employed so that they can be removed
at later stages in a synthetic sequence. Thus, benzyl ethers
are often employed as ‘long-term’ protecting groups carried
through multiple steps in a synthetic sequence. On the other
hand, substituted benzyl ethers are deliberately less stable,
In this direction, we envisioned a new protecting group, the
trimethylsilyl xylyl ether (TIX), which can be attached to a
hydroxyl group efficiently and selectively removed in the
presence of other groups under mild conditions. Further-
more, as one procedural iteration involves a polymer-
supported reagent during preparation of the reagent 2
for protection, it can also be beneficially applied to
solution-phase parallel chemistry using solid-phase reagents
during generation of parallel libraries.
Keywords: Trimethylsilyl xylyl; Protecting groups; Ethers.
* Corresponding author. Tel.: C1 662 915 5879; fax: C1 662 915 5638;
e-mail: mavery@olemiss.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.023

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C. R. Reddy et al. / Tetrahedron 61 (2005) 1289–1295
2. Results and discussion
The imidate 2, thus formed, would then be purified by
chromatography or distillation. However, in our hands, this
imidate was insufficiently stable to silica gel chromato-
graphy, so we opted to proceed without further purification.
Thus 1, after reaction with DBU, was treated with the
alcohol followed by a slight excess (with respect to DBU)
of p-toluenesulfonic acid (pTSA) or its pyridinium salt
(PPTS). The yields in these cases were moderate to good,
but unreacted alcohols (1 and ROH) were present,
undoubtedly due to the presence of traces of water or
other contaminants associated with the combining of
reaction steps.
Hence, the TIX group was easily introduced onto a hydroxyl
moiety using a one-pot trichloroacetimidate protocol.6 The
known silyl alcohol 17 was initially converted to its
trichloroacetimidate derivative 2 using literature precedent
in which Cl3CCN, the alcohol 1, and DBU were combined.
To forestall lengthy low-yielding purifications of imidate 2,
we took advantage of solid-supported chemistries now
readily available. Thus, reaction of 1 with a commercially
available polymer-supported base related to DBU, 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (PS-TBD), in the presence of
Cl3CCN in dichloromethane at 0 8C followed by a simple
filtration furnished essentially pure imidate 2. For catalysis
of the ensuing ether formation with ROH 4, because no
DBU was present to contend with, harsh, hygroscopic
sulfonic acids could be eliminated and a catalytic amount of
Scheme 1.
Table 1. TIX protection of alcoholsa
Entry
1
Alcohol
Product
Isolated yield (%)
81, 80b
4a
4b
5a
5b
2
82
3
4
5
4c
4d
4e
5c
5d
5e
88
76, 78b
91
6
7
4f
5f
79
80
4g
5g
8
4h
5h
92
9
RZBn
p-xylyl
PMB
SEM
Ac
Bz
TBDMS
TBDPS
MEM
4i
4j
4k
4l
4m
4n
4o
4p
4q
RZBn
p-xylyl
PMB
SEM
Ac
Bz
TBDMS
TBDPS
MEM
5i
5j
5k
5l
5m
5n
5o
5p
5q
82
91
78
80
82
95
10
11
12
13
14
15
16
17
85, 87b
80
80
a Conditions: imidate 2, Sc(OTf)3 (2 mol%), CH2Cl2, 0 8C to rt, 15 min.
b Yields under basic conditions: bromide 3, NaH, THF, rt, 2–5 h.

C. R. Reddy et al. / Tetrahedron 61 (2005) 1289–1295
Table 2. Removal of TIX group under various conditions
1291
Entry
1
Reagent
Solvent/temp (8C)
Time (h)
0.25
Product
Isolated yield (%)
TFA (20 equiv)
CH2Cl2/0
4a
52
2
3
n-BU4NF
THF/rt
0.5
2.5
94
4a0
CsF
DMF/90a
88
4a0
4
5
6
7
8
9
HF-pyridine
BF3$Et2O
ZnCl2
MgBr2–Et2O, Me2S
CAN
DDQ
THF/rt
CH2Cl2/rt
CH2Cl2/rt
CH2Cl2/rt
THF–H2O (9:1)/rt
CH2Cl2–H2O (9:1)/rt
4
2
2
3
0.5
0.25
No reaction
No reaction
No reaction
No reaction
4a
—
—
—
—
62
91
4a
a No reaction at rt.
a mild Lewis acid such as scandium triflate could be
usefully employed instead to furnish the protected com-
pound 5 in good to excellent yields. Since acid sensitive
groups are unstable under the above reaction conditions for
the protection of alcohols, we have also prepared the
bromide 3 and used it to protect the hydroxyl group as the
TIX ether 5 under basic conditions using NaH (Scheme 1).
The TIX group was installed without generally affecting the
other protecting groups (Table 1).
After developing the new protecting group, its removal was
investigated. Accordingly, 3-phenyl-1-propanol TIX ether
5a was initially treated with TFA leading to the formation of
the deprotected alcohol 4a in low yields. Furthermore,
removal of contaminants was found to be quite difficult.
Among the by-products were high-Rf aromatic compounds
that presumably resulted from facile polymerization of
p-quinone dimethide (p-xylylene).8 We also used certain
fluoride reagents, Lewis acids and oxidizing agents, the
results of which are summarized in Table 2. Among these,
DDQ provided a mild and chemoselective oxidative
cleavage of the TIX moiety in the presence of other
functionalities and protecting groups. Entry 7 demonstrates
that the deprotection of 5g occurred with the retention of
stereochemistry to produce the 4g in 83% yield. This
deprotection method resulted in high yields, adding an
advantage to the use of this protecting group compared to its
removal under acidic conditions (Table 3).
To check for generality and functional group compatibility,
the protection reaction was performed on a variety of
alcohols, for example, 1, 2, 38, benzylic, allylic and
anomeric, bearing functionalities such as a b-keto group,
an enone, olefin, acetylenic unit, or a variety of other
protecting groups. To examine the issue of the chemoselec-
tivity of these protection conditions, 1,6-hexanediol was
differentially protected on one side with TBDMS, TBDPS,
SEM, benzyl, PMB, ester, etc., while the remaining
hydroxyl group was subjected to the protection protocol.
Table 3. Removal of TIX group using DDQa
Since the cleavage of the TIX group is similar to the PMB
group, we were interested in studying the stability of the
TIX ether over the PMB ether (Table 4). We subjected 5k to
typical PMB ether deprotection conditions and observed
that in most cases the TIX group was stable. Using ZrCl4 in
CH3CN, the PMB group could be selectively removed in the
presence of TIX in 95% yield. Furthermore, the TIX group
in PMBO–(CH2)6–OTIX 5k could be selectively cleaved
with DDQ at K10 8C leaving the PMB in place, giving
PMB–(CH2)6–OH 4k in 74% yield. The TIX group is stable
under commonly used basic conditions such as LDA and
n-BuLi (Tables 2 and 4). As expected, cleavage of both
PMB and TIX occurs under catalytic hydrogenation
conditions.
Entry
TIX ether
Alcohol
Isolated yield (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
4a
4b
4c
4d
4e
4f
4g
4h
4i
91
82
74
84
71
81
83
87
92
93
90
89
92
93
91
88
9
10
11
12
13
14
15
16
5j
5l
4j
4l
5m
5n
5o
5p
5q
4m
4n
4o
4p
4q
Mechanistically, cleavage of the TIX group by DDQ is
likely to be similar to that of the PMB group; for, in all the
cases, we could isolate p-trimethylsilylmethyl benzaldehyde
6 as a by-product. As shown in Scheme 2, the silyl group
enhances the rate of benzyl ether cleavage relative to a
a Aldehyde 6 could be isolated in each case.

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C. R. Reddy et al. / Tetrahedron 61 (2005) 1289–1295
Table 4. Stability of the TIX ether over the PMB ether
Entry
Reagent
Solvent/temp (8C)
Time (h)
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
5% TFA4a
LiBF4 (10 mol%)
ZrCl4 (20 mol%)4b
CeCl3$7H2O, NaI4c
AcOH4d
LDA
BuLi
DDQ
CH2Cl2/0
CH3CN/reflux
CH3CN/rt
CH3CN/reflux
—/90
THF/K30 to rt
THF/0 to rt
CH2Cl2–H2O (9:1)/K10
0.5
2
0.75
15
0.5
5
80a
90
94
76a
78
—
—
74
4k0
4k0
4k0
4k0
4k0
No reaction
No reaction
4k
6
0.25
9
H2–Pd/C
EtOH/rt
2
48
a 5–10% of 4k also observed.
non-silylated version (i.e., the p-xylyl benzyl ether 5j or
simple benzyl ether 5i, Table 1) by stabilization of A and/or
by the transition state leading to A. The resultant
intermediate A is then captured by water to furnish a
hemiacetal B that undergoes reversal to aldehyde 6 and the
desired deprotected alcohol 4. The exact mechanism by
which DDQ accepts the benzylic proton of 5, leading to A is
a matter of debate.9
Furthermore, DDQ was quite selective for the rapid removal
of the TIX group in the presence of a p-methylbenzyl group
as had been the case for the benzyl ether (entries 8–10 in
Table 3).
3. Conclusion
We expect that the TIX group will prove to be a new ‘PMB-
like’ versatile protecting group for hydroxyl functions in
natural product synthesis and carbohydrate chemistry. It can
be introduced under both acidic and basic reaction
conditions and removed with DDQ, even in the presence
of other commonly used protecting groups. The stability of
the TIX group towards acidic as well as basic conditions is
an added advantage.
Scheme 2.
To further assess the role of the silyl group in both
protection and deprotection steps, we prepared a few
representative p-methylbenzyl (xylyl) ethers. Surprisingly,
while p-methylbenzyl alcohol readily underwent imidate
formation, it was reluctant to undergo acid-catalyzed ether
formation with comparable, or even marginally similar,
efficacy compared to the TIX group. This fact implied that
the protection step was promoted by the presence of the
1,6-silyl group and presumably by a mechanism reminiscent
of the deprotection step outlined in Scheme 2. Thus, the fact
that p-methylbenzyl ethers would not form in acceptable
yields or at acceptable rates with either 0.02 or even
0.10 mol equiv of scandium triflate, while imidate 2 reacted
rapidly and cleanly with 0.02 mol equiv (entry 10, Table 1),
strongly implicated a silyl-assisted transition state for the
protection step (Scheme 3).
4. Experimental
4.1. General
All reactions were carried out under an argon atmosphere,
unless otherwise stated. Thin layer chromatography (TLC)
was performed on precoated silica gel G and GP Uniplates.
The plates were visualized with a 254-nm UV light, iodine
chamber, or charring with acid. Flash chromatography was
carried out on silica gel 60 (particle size 32–63 mm, pore
size 60 A). H NMR and 13C NMR spectra were recorded in
˚
1
CDCl3 at 400 and 100 MHz, respectively. The chemical
shifts are reported in parts per million (ppm) downfield from
tetramethylsilane, and J-values are in Hz. IR spectra were
recorded on FT-IR spectrometer on a germanium crystal
plate as neat solids or liquids. The high-resolution mass
spectra (HRMS) were recorded on a Waters/Micromass
Q-TOF Micro mass spectrometer with ESI lock spray
source. Dry dichloromethane was prepared by distilling it
over calcium hydride. Commercially available polystyrene-
bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (PS-TBD), tri-
chloroacetonitrile and scandium (III) triflate were used
directly without further purification. The trimethylsilyl
alcohol 1 was prepared in two steps starting from the
commercially available 4-bromobenzyl bromide using the
literature procedure.7
Scheme 3.

C. R. Reddy et al. / Tetrahedron 61 (2005) 1289–1295
1293
4.2. General procedure for the TIX protection of the
alcohols
7.19 (d, JZ7.6 Hz, 2H), 6.95 (d, JZ8 Hz, 2H), 5.86–5.78
(m, 2H), 4.51 (dd, JZ11.6 Hz, 2H), 3.94 (bs, 1H), 2.05 (s,
2H), 1.96–1.72 (m, 6H), 0.03 (s, 9H); 13C NMR (CDCl3): d
140.0, 134.6, 131.3 (2C), 128.2 (2C), 128 (2C), 72.3, 70.3,
28.6, 27.0, 25.5, 19.5, K1.7 (3C); IR (neat): 845, 1076,
1246, 1504, 2951 cmK1; HRMS (ESI): calcd for
C17H26OSi, 297.1645 (MCNa)C, found 297.1647.
PS-TBD (250 mg/mmol of 1) was suspended in dry
dichloromethane (5 mL/mmol of 1) under argon at 0 8C,
to which silyl alcohol 1 (1 mol equiv) was added. After
stirring for 5 min at 0 8C, trichloroacetonitrile (1 mol equiv)
was added. The reaction mixture was brought to room
temperature and stirred for 15 min. The organic solution
was separated from the polymer beads, and the clear
dichloromethane solution of 2 was then cooled to 0 8C. One
molar equivalent of a representative alcohol 4 was added
followed by scandium triflate (0.02 mol equiv). The reaction
mixture was stirred at room temperature for 15 min and
diluted with dichloromethane (15 mL/mmol). The organic
layer was washed with water and brine, dried (anhydrous
Na2SO4), and concentrated. Simple purification was accom-
plished by flash column chromatography over silica gel
using EtOAc/hexanes, providing the TIX ethers 5 in good
yields (Table 1).
4.2.6. Trimethyl(4-{[(1-methylcyclohexyl)oxy]methyl}-
benzyl)silane (5e). Colorless oil; 1H NMR (CDCl3): d
7.20 (d, JZ7.6 Hz, 2H), 6.95 (d, JZ7.6 Hz, 2H), 4.35 (s,
2H), 2.05 (s, 2H), 1.83–1.78 (m, 2H), 1.68–1.62 (m, 2H),
1.46–1.25 (m, 6H), 1.22 (s, 3H), K0.02 (s, 9H); 13C NMR
(CDCl3): d 139.4, 135.6, 128.2 (2C), 127.5 (2C), 74.0, 62.9,
36.8 (2C), 26.9, 26.0, 25.1, 22.5 (2C), K1.7 (3C); IR (neat):
847, 1068, 1123, 1245, 2856, 2921 cmK1; HRMS (ESI):
calcd for C18H30OSi, 313.1964 (MCNa)C, found
313.1959.
4.2.7. 3-Ethyl-4,4-dimethyl-5-({4-[(trimethylsilyl)-
methyl]benzyl}oxy)cyclohex-2-en-1-one (5f). Colorless
1
4.2.1. 4-[(Trimethylsilyl)methyl]benzyl 2,2,2-trichloro-
ethanimidoate (2). Colorless oil which upon standing at
room temperature to give colorless crystals, mp 32–35 8C;
1H NMR (CDCl3): d 8.41 (bs, 1H), 7.32 (d, 2H, JZ7.9 Hz),
7.05 (d, 2H, JZ7.9 Hz), 5.32 (s, 2H), 2.13 (s, 2H), 0.04 (s,
9H); 13C NMR (CDCl3): d 162.7, 140.9, 130.9, 129.2, 128.1
(2C), 127.9 (2C), 71.0, 27.0, K1.9 (3C); IR (neat): 645, 841,
oil; H NMR (CDCl3): d 7.15 (d, JZ8 Hz, 2H), 6.95 (d,
JZ7.6 Hz, 2H), 5.83 (s, 1H), 4.59 (d, JZ11.6 Hz, 1H), 4.36
(d, JZ11.2 Hz, 1H), 3.54 (dd, JZ4, 8 Hz, 1H), 2.73 (dd,
JZ4, 16 Hz, 1H), 2.57 (dd, JZ8.8, 16.8 Hz, 1H), 2.26
(distorted doublet JZ6.8 Hz, 2H), 2.06 (s, 2H), 1.16 (d, JZ
4.8 Hz, 6H), 1.08 (t, JZ7.2, 14.4 Hz, 3H), K0.02 (s, 9H);
13C NMR (CDCl3): d 197.9, 172.8, 140.3, 133.7, 128.2 (2C),
128.1 (2C), 123.7, 81.3, 71.6, 39.1, 29.9, 27.0, 25.0, 24.6,
21.5, 11.8, K1.70 (3C); IR (neat): 850, 1075, 1245, 1664,
2921, 2951 cmK1; HRMS (ESI): calcd for C21H32O2Si,
345.2250 (MCH)C, found 345.2241.
1074, 1294, 1662, 2953 cmK1
.
4.2.2. Trimethyl{4-[(3-phenylpropoxy)methyl]benzyl}-
silane (5a). Colorless oil; H NMR (CDCl3): d 7.32–7.21
1
(m, 7H), 7.01 (d, JZ7.6 Hz, 2H), 4.47 (s, 2H), 3.51 (t, JZ
6 Hz, 11.6 Hz, 2H), 2.74 (t, JZ7.6, 15.2 Hz, 2H), 2.10 (s,
2H), 1.98–1.94 (m, 2H), 0.02 (s, 9H); 13C NMR (CDCl3): d
142.3, 140.1, 134.2, 128.7 (2C), 128.5 (2C), 128.3 (2C),
128.1 (2C), 126.0, 73.2, 69.6, 32.7, 31.6, 27.0, K1.66 (3C);
IR (neat): 851, 1099, 1246, 2921, 2951 cmK1; HRMS (ESI):
calcd for C20H28OSi, 335.1801 (MCNa)C, found 335.1803.
4.2.8.
(K)-4S-5,5-Dimethyl-4-({4-[(trimethylsilyl)-
methyl]benzyl}oxy)octane-2,6-dione (5g). Colorless oil;
[a]2D5ZK38.76 (cZ0.56, CHCl3); 1H NMR (CDCl3): d
7.08 (d, JZ8 Hz, 2H), 6.93 (d, JZ8 Hz, 2H), 4.42 (dd, JZ
11.2, 29.6 Hz, 2H), 4.25 (dd, JZ3.2, 7.2 Hz, 1H), 2.62 (dd,
JZ7.6, 17.2 Hz, 1H), 2.54–2.46 (m, 3H), 2.14 (s, 3H), 2.04
(s, 2H), 1.15 (s, 3H), 1.10 (s, 3H), 0.98 (t, JZ6.8, 14, 7.2 Hz,
3H), K0.03 (s, 9H); 13C NMR (CDCl3): d 215.6, 207.5,
140.1, 134.1, 128.1 (2C), 127.8 (2C), 79.7, 73.8, 52.2, 45.9,
31.9, 27.0, 23.9, 21.2, 21.1, 8.07, K1.7 (3C); IR (neat): 847,
1075, 1245, 1705, 2951 cmK1; HRMS (ESI): calcd for
C21H34O3Si, 385.2175 (MCNa)C, found 385.2180.
4.2.3. Trimethyl{4-[(1-phenylethoxy)methyl]benzyl}-
silane (5b). Colorless oil; H NMR (CDCl3): d 7.38 (d,
1
2H), 7.30–7.23 (m, 3H), 7.16 (d, 2H, JZ7.6 Hz), 6.97 (d,
2H, JZ7.6 Hz), 4.51 (m, 1H), 4.40 (d, 1H, JZ11.4 Hz),
4.25 (d, 1H, JZ11.6 Hz), 2.07 (s, 2H), 1.48 (d, 3H, JZ
6.4 Hz), K0.006 (s, 9H); 13C NMR (CDCl3): d 144.0, 139.8,
133.9, 128.8 (2C), 128.1 (2C); 127.9 (2C); 127.5, 126.5
(2C), 77.2, 70.5, 26.9, 24.4, K1.8 (3C); IR (neat): 760, 845,
4.2.9. 4-[(Trimethylsilyl)methyl]benzyl 2,3,4,6-tetra-O-
benzylhexopyranoside (5h). Colorless oil; 1H NMR
(CDCl3): d 7.31–7.19 (m, 20H), 7.14 (d, JZ7.6 Hz, 2H),
6.98 (d, JZ7.6 Hz, 2H), 5.03–4.81 (m, 4H), 4.73–4.46 (m,
6H), 4.05 (t, JZ9.2, 18.4 Hz, 1H), 3.83–3.56 (m, 6H), 2.1
(s, 2H), 0.01 (s, 9H); 13C NMR (CDCl3): d 140.4, 139.0,
138.4, 138.3, 138.1, 132.6, 128.8 (2C), 128.5 (8C), 128.1
(4C), 128.05 (4C), 128.0 (4C), 127.8, 127.7, 95.3, 82.3,
79.9, 77.8, 75.8, 75.1, 73.5, 72.8, 70.4, 69.2, 68.5, 26.9,
K1.7 (3C); IR (neat): 702, 845, 1078, 1245, 1458,
1107, 1246, 1511, 2889 cmK1
.
4.2.4. Trimethyl(4-{[(1-methylprop-2-yn-1-yl)oxy]-
methyl}benzyl)silane (5c). Colorless oil; 1H NMR
(CDCl3): d 7.24 (d, 2H, JZ7.6 Hz), 7.01 (d, 2H, JZ
7.6 Hz), 4.76 (d, 1H, JZ11.2 Hz), 4.47 (d, 1H, JZ11.2 Hz),
4.25–4.22 (m, 1H), 2.48 (s, 1H), 2.10 (s, 2H), 1.93 (d, 3H,
JZ6.8 Hz), 0.01 (s, 9H); 13C NMR (CDCl3): d 140.1, 133.0,
128.1 (2C), 127.9 (2C), 83.7, 73.0, 70.4, 63.9, 26.7, 22.0,
K2.0 (3C); IR (neat): 850, 1103, 1250, 1516, 2962,
3294 cmK1; HRMS (ESI): calcd for C15H22OSi, 269.1333
(MCNa)C, found 269.1344.
2892 cmK1
; HRMS (ESI): calcd for C45H52O6Si,
739.3431 (MCNa)C, found 739.3394.
4.2.10. [4-({[6-(Benzyloxy)hexyl]oxy}methyl)benzyl](tri-
methyl)silane (5i). Colorless oil; 1H NMR (CDCl3): d 7.36–
7.25 (m, 5H), 7.20 (d, JZ8 Hz, 2H), 6.98 (d, JZ8 Hz, 2H),
4.52 (s, 2H), 4.45 (s, 2H), 3.50–3.45 (m, 4H), 2.08 (s, 2H),
4.2.5. {4-[(Cyclohex-2-en-1-yloxy)methyl]benzyl}(tri-
methyl)silane (5d). Colorless oil; 1H NMR (CDCl3): d

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C. R. Reddy et al. / Tetrahedron 61 (2005) 1289–1295
1.66–1.62 (m, 4H), 1.42–1.39 (m, 4H), K0.05 (s, 9H); 13
C
166.7, 139.8, 134.0, 132.8, 130.5, 129.6 (2C), 128.5, 128.3,
128.0 (2C), 127.8 (2C), 72.9, 70.2, 65.0, 29.7, 28.7, 26.8,
26.0 (2C), K1.9 (3C); IR (neat): 711, 854, 1107, 1275,
1720, 2856, 2946 cmK1; HRMS (ESI): calcd for
C24H34O3Si, 421.2175 (MCNa)C, found 421.2184.
NMR (CDCl3): d 140.0, 138.9, 134.8, 128.6 (2C), 128.3,
128.2, 128.0 (2C), 127.9 (2C), 127.7, 73.1 (2C), 70.6, 70.5,
30.0 (2C), 27.0, 26.3 (2C), K1.7 (3C); IR (neat): 847, 1099,
1242, 2853, 2931 cmK1; HRMS (ESI): calcd for
C24H36O2Si, 407.2382 (MCNa)C, found 407.2371.
4.2.16. tert-Butyl(dimethyl){[6-({4-[(trimethylsilyl)-
methyl]benzyl}oxy)hexyl]oxy}silane (5o). Colorless oil;
1H NMR (CDCl3): d 7.17 (d, 2H, JZ7.6 Hz), 6.96 (d, 2H,
JZ7.6 Hz), 4.43 (s, 2H), 3.60 (t, 2H, JZ6.4 Hz), 3.45 (t,
2H, JZ6.4 Hz), 2.07 (s, 2H), 1.3–1.58 (m, 2H), 1.55–1.50
(m, 2H), 1.40–1.31 (m, 4H), 0.89 (s, 9H), 0.04 (s, 6H),
K0.02 (s, 9H); 13C NMR (CDCl3): d 140.0, 134.3, 128.2
(2C), 128.0 (2C), 73.1, 70.5, 63.4, 33.1, 30.0, 27.0, 26.2
(3C), 25.9, 25.8, 18.6, K1.7 (3C), K5.0 (2C); IR (neat):
776, 858, 1099, 1250, 2856, 2933 cmK1; HRMS (ESI):
calcd for C23H44O2Si2, 447.2517 (MCNa)C, found
447.2513.
4.2.11. Trimethyl{4-[({6-[(4-methylbenzyl)oxy]hexyl}-
oxy)methyl]benzyl}silane (5j). Colorless oil; 1H NMR
(CDCl3): d 7.23 (d, 2H, JZ7.6 Hz), 7.18 (d, 2H, JZ7.6 Hz),
7.15 (d, 2H, JZ7.6 Hz), 6.97 (d, 2H, JZ7.6 Hz), 4.46 (s,
2H), 4.44 (s, 2H), 3.45 (dd, 4H, JZ6.4 Hz), 2.34 (s, 3H),
2.07 (s, 2H), 1.60 (m, 4H), 1.38 (m, 4H), K0.02 (s, 9H); 13C
NMR (CDCl3): d 139.8, 137.1, 135.7, 134.1, 129.0 (2C),
128.0 (2C), 127.8 (2C), 127.8 (2C), 72.9, 72.8, 70.3, 70.2,
29.7, 27.1, 26.8, 26.1 (2C), 21.2, K1.8 (3C); IR (neat): 694,
857, 1098, 1245, 1507, 2949 cmK1; HRMS (ESI): calcd for
C25H38O2Si, 437.2278 (MCK)C, found 437.2263.
4.2.12.
{4-[({6-[(4-Methoxybenzyl)oxy]hexyl}oxy)-
4.2.17. tert-Butyl(diphenyl){[6-({4-[(trimethylsilyl)-
methyl]benzyl}oxy)hexyl]oxy}silane (5p). Colorless oil;
1H NMR (CDCl3): d 7.70 (m, 4H), 7.41 (m, 6H), 7.21 (d,
2H, JZ7.6 Hz), 6.99 (d, 2H, JZ8.4 Hz), 4.46 (s, 2H), 3.68
(t, 2H, JZ6.4 Hz), 3.47 (t, 2H, JZ6.4 Hz), 2.09 (s, 2H),
1.67–1.57 (m, 4H), 1.44–1.30 (m, 4H), 1.07 (s, 9H), 0.01 (s,
9H); 13C NMR (CDCl3): d 140.0, 135.8 (4C), 134.5 (4C),
134.4 (2C), 129.8 (2C), 128.3 (2C), 128.0, 127.9 (2C), 73.2,
70.6, 64.2, 32.8, 30.1, 27.2 (3C), 27.1, 26.3, 26.0, 19.5.
K1.6 (3C).; IR (neat): 702, 845, 1107, 1246, 1511, 2852,
2933 cmK1; HRMS (ESI): calcd for C33H48O2Si2, 571.2830
(MCK)C, found 571.2850.
methyl]benzyl}(trimethyl)silane (5k). Colorless oil; 1H
NMR (CDCl3): d 7.29 (d, 2H, JZ8.4 Hz), 7.21 (d, 2H, JZ
7.6 Hz), 6.99 (d, 2H, JZ7.6 Hz), 6.90 (d, 2H, JZ8.4 Hz),
4.46 (s, 4H), 3.83 (s, 3H), 3.46 (dd, 4H, JZ6.4, 13.2 Hz),
2.09 (s, 2H), 1.68–1.60 (m, 4H), 1.42–135 (m, 4H), 0.01 (s,
9H); 13C NMR (CDCl3): d 159.1, 139.8, 134.0, 130.8, 129.2
(2C), 127.9 (2C), 127.7 (2C), 113.7 (2C), 72.8, 72.5, 70.3,
70.1, 55.3, 29.7 (2C), 26.8, 26.1 (2C), K1.9 (3C); IR (neat):
845, 1099, 1246, 1511, 2856, 2933 cmK1; HRMS (ESI):
calcd for C25H38O3Si, 437.2488 (MCNa)C, found
437.2470.
4.2.13. 2,2-Dimethyl-15-{4-[(trimethylsilyl)methyl]-
phenyl}-5,7,14-trioxa-2-silapentadecane (5l). Colorless
oil; H NMR (CDCl3): d 7.17 (d, JZ7.6 Hz, 2H), 6.95 (d,
4.2.18. Trimethyl[4-(2,9,11,14-tetraoxapentadec-1-yl)-
benzyl]silane (5q). Colorless oil; 1H NMR (CDCl3): d
7.17 (d, 2H, JZ7.6 Hz), 6.96 (d, 2H, JZ7.6 Hz), 4.70 (s,
2H), 4.42 (s, 2H), 3.68 (t, 2H, JZ6.4 Hz), 3.56–3.51 (m,
4H), 3.45 (t, 2H, JZ6.4 Hz), 2.06 (s, 2H), 1.61–1.57 (m,
4H), 1.41–1.34 (m, 4H), K0.02 (s, 9H). 13C NMR (CDCl3):
d 139.8, 134.0, 128.0 (2C), 127.7 (2C), 95.5, 72.9, 71.8,
70.3, 67.9, 66.7, 59.0, 29.7, 29.6, 26.8, 26.1, 26.0, K1.9
1
JZ7.6 Hz, 2H), 4.65 (s, 2H), 4.42 (s, 2H), 3.60 (t, JZ8.4,
16.8 Hz, 2H), 3.52 (t, JZ6.8, 13.2 Hz, 2H), 3.45 (t, JZ6.8,
13.2 Hz, 2H), 2.06 (s, 2H), 1.61–1.56 (m, 4H), 1.38–1.25
(m, 4H), 0.93 (t, JZ8.4, 16.8 Hz, 2H), 0.01 (s, 9H), K0.02
(s, 9H); 13C NMR (CDCl3): d 140.0, 134.2, 128.2 (2C),
128.0 (2C), 95.0, 73.1, 70.5, 68.0, 65.1, 29.9 (2C), 27.0,
26.3, 26.2, 18.3, K1.2 (3C), K1.7 (3C); IR (neat): 854,
1061, 1106, 12.52, 2863, 2945 cmK1; HRMS (ESI): calcd
for C23H44O3Si2, 447.2727 (MCNa)C, found 447.2726.
(3C); IR (neat): 853, 1045, 1106, 1249, 1511, 2933 cmK1
;
HRMS (ESI): calcd for C21H38O4Si, 421.2176 (MCK)C,
found 421.2159.
4.3. General procedure for the deprotection of TIX
ethers
4.2.14. 6-({4-[(Trimethylsilyl)methyl]benzyl}oxy)hexyl
acetate (5m). Colorless oil; H NMR (CDCl3): d 7.20 (d,
1
2H, JZ7.6 Hz), 6.99 (d, 2H, JZ7.6 Hz), 4.46 (s, 2H), 4.07
(t, 2H, JZ6.4 Hz), 3.48 (t, 2H, JZ6.4 Hz), 2.09 (s, 2H),
2.06 (s, 3H), 1.70–1.62 (m, 4H), 1.46–1.36 (m, 4H), 0.00 (s,
9H); 13C NMR (CDCl3): d 171.2, 139.8, 134.0, 128.0 (2C),
127.7 (2C); 72.9, 70.1, 64.5, 29.6, 28.6, 26.8, 25.9, 25.8,
21.0, K1.9 (3C); IR (neat): 854, 1103, 1246, 1740, 2860,
2950 cmK1; HRMS (ESI): calcd for C19H32O3Si, 359.2018
(MCNa)C, found 359.2027.
The TIX ether (1 mol equiv) was taken in dichloromethane:
water (9:1 or 5 mL/mmol). To this well stirred solution was
added DDQ (1 mol equiv) at room temperature (generally
15–60 min). After completion of the reaction (as monitored
by TLC for disappearance of starting material), the reaction
mixture was filtered, and the filtrate was washed with
dichloromethane (10 mL). The combined organic layers
were washed with a saturated aqueous solution of NaHCO3,
brine, dried (anhydrous Na2SO4), filtered and concentrated.
Purification of the residue was readily achieved by flash
column chromatography (silica gel 60, EtOAc/hexanes)
affording the alcohols in excellent yields (Table 3).
4.2.15. 6-({4-[(Trimethylsilyl)methyl]benzyl}oxy)hexyl
benzoate (5n). Colorless oil; H NMR (CDCl3): d 8.07 (d,
1
2H, JZ7.2 Hz), 7.58 (t, 1H, JZ7.6 Hz), 7.46 (t, 2H, JZ
7.2 Hz), 7.20 (d, 2H, JZ7.6 Hz), 6.99 (d, 2H, JZ7.6 Hz),
4.47 (s, 2H), 4.34 (t, 2H, JZ6.4 Hz), 3.50 (t, 2H, JZ
6.4 Hz), 2.09 (s, 2H), 1.83–1.76 (m, 2H), 1.70–1.62 (m, 2H),
1.54–1.42 (m, 4H), 0.01 (s, 9H); 13C NMR (CDCl3): d
4.3.1. 1-Methyl-4-[(3-phenylpropoxy)methyl]benzene
1
(4a0). Colorless oil; H NMR (CDCl3): d 7.36–7.22 (m,
9H), 4.54 (s, 2H), 3.54 (t, 2H, JZ6.4 Hz), 2.78 (t, 2H, JZ

C. R. Reddy et al. / Tetrahedron 61 (2005) 1289–1295
1295
7.2 Hz); 2.42 (s, 3H); 2.03–1.96 (m, 2H); 13C NMR
(CDCl3): d 142.1, 137.3, 135.6, 129.1 (2C), 128.6 (2C),
128.4 (2C), 127.9 (2C), 125.8, 72.9, 69.4, 32.5, 31.5, 21.3;
Pavia, A. A. Tetrahedron Lett. 2000, 41, 2891. (c) Sharma,
G. V. M.; Rakesh. Tetrahedron Lett. 2001, 42, 5571.
3. (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron
Lett. 1982, 23, 885. (b) Tanaka, T.; Oikawa, Y.; Hamada, T.;
Yonemitsu, O. Tetrahedron Lett. 1986, 27, 3651. (c) Horita,
K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021. (d) Oikawa, Y.; Tanaka, T.;
Horita, K.; Yonemitsu, O. Tetrahedron Lett. 1984, 25, 5397.
4. (a) Yan, L.; Kahne, D. E. Synlett 1995, 523. (b) Sharma,
G. V. M.; Reddy, Ch. G.; Krishna, P. R. J. Org. Chem. 2003,
68, 4574 and references cited therein. (c) Cappa, A.;
Marcantoni, E.; Torregiani, E. J. Org. Chem. 1999, 64, 5696.
(d) Hodgetts, K. J.; Wallace, T. W. Synth. Commun. 1994, 24,
1151. (e) Onoda, T.; Shirai, R.; Iwasaki, S. Tetrahedron Lett.
1997, 38, 1443. (f) Bouzide, A.; Sauve, G. Synlett 1997, 1153.
5. (a) Jobron, L.; Hindsgaul, O. J. Am. Chem. Soc. 1999, 121,
5835. (b) Plante, O. J.; Buchwald, S. L.; Seeberger, P. H.
J. Am. Chem. Soc. 2000, 122, 7148.
IR (neat): 702, 845, 1107, 1246, 1511, 2852, 2933 cmK1
;
HRMS (ESI): calcd for C17H20O, 279.4384 (MCK)C,
found 279.4388.
4.3.2. 6-[(4-Methylbenzyl)oxy]hexan-1-ol (4j). Colorless
1
oil; H NMR (CDCl3): d 7.22 (d, 2H, JZ7.6 Hz), 7.15
(d, 2H, JZ7.6 Hz), 4.45 (s, 2H), 3.62 (t, 2H, JZ6.4 Hz),
3.44 (t, 2H, JZ6.4 Hz), 2.34 (s, 3H), 2.07 (s, 2H), 1.63–1.54
(m, 4H), 1.43–1.37 (m, 4H); 13C NMR (CDCl3): d 137.2,
135.4, 129.1 (2C), 127.8 (2C), 72.7, 70.2, 62.6, 32.6, 29.7,
26.0, 25.6, 21.2; IR (neat): 681, 804, 1074, 1262, 2945,
3374 cmK1
.
4.3.3. 6-({4-[(Trimethylsilyl)methyl]benzyl}oxy)hexan-1-
ol (4k0). Colorless oil; 1H NMR (CDCl3): d 7.19 (d, 2H, JZ
7.6 Hz), 6.98 (d, 2H, JZ7.6 Hz), 4.46 (s, 2H), 3.65 (t, 2H,
JZ6.4 Hz), 3.48 (t, 2H, JZ6.4 Hz), 2.08 (s, 2H), 1.63–1.58
(m, 4H), 1.46–1.37 (m, 4H), 0.00 (s, 9H); 13C NMR
(CDCl3): d 139.8, 133.7, 127.9 (2C), 127.7 (2C), 72.8, 70.1,
62.6, 32.5, 29.5, 25.8, 25.5, 25.4, K2.0 (3C); IR (neat): 858,
1107, 1246, 1687, 2856, 2938, 3370 cmK1; HRMS (ESI):
calcd for C17H30O2Si, 333.1652 (MCK)C, found 333.1659.
6. Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267 and
references cited therein.
7. d’Alessandro, N.; Albini, A.; Mariano, P. S. J. Org. Chem.
1993, 58, 937.
8. (a) Szunerits, S.; Utley, J. H. P.; Nielsen, M. F. J. Chem. Soc.,
Perkin Trans. 2 2000, 4, 669.(b) Quinodimethane polymers.
Green, George David. Univ. Arizona, Tucson, AZ, USA.
Avail. Univ. Microfilms Int., Order No. DA8623849. 1986, p
79. From: Diss. Abstr. Int. B. 1987, 47, 2914. (c) Lasne, M. C.;
Ripoll, J. L.; Denis, J. M. Tetrahedron 1981, 37, 503.
(d) Tseng, K. L.; Michl J. Am. Chem. Soc. 1977, 99, 4840.
9. (a) Lee-Ruff, E.; Ablenas, F. J. Can. J. Chem. 1989, 67, 699.
(b) Ohki, A.; Nishiguchi, T.; Fukuzumi, K. Tetrahedron 1979,
35, 1737.
4.3.4. 4a to 4e,10 4f and 4g,11 4h,10 4i,12 4k,13 4l,14 4m,15
4n,16 4o and 4p,17 4q18 and 6.19 1H NMR, IR and mass
spectral data of these known compounds were identical with
those of authentic samples.
10. Aldrich catalogue, 2003–2004.
Acknowledgements
11. Zheng, Y.; Avery, M. A. Tetrahedron 2004, 60, 2091.
12. Quici, S.; Manfredi, A.; Raimondi, L.; Sironi, A. J. Org. Chem.
1995, 60, 6379.
We thank Tapestry Pharmaceuticals (formerly NaPro
Biotherapeutics, Inc.) for financial support.
13. Hu, T.-S.; Yu, Q.; Wu, Y.-L.; Wu, Y. J. Org. Chem. 2001, 66,
853.
14. Chen, M.-Y.; Lee, A. S.-Y. J. Org. Chem. 2002, 67, 1384.
15. Srinivas, K. V. N. S.; Mahender, I.; Das, B. Synlett 2003, 2419.
16. Iwasaki, F.; Maki, T.; Onomura, O.; Nakashima, W.;
Matsumura, Y. J. Org. Chem. 2000, 65, 996.
References and notes
1. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Chemistry, 3rd ed.; Wiley: New York, 1999.
(b) Kocienski, P. J. Protecting Groups; Thieme: Stuggart,
1994.
17. McDougal, P. G.; Rico, J. G.; Oh, Y. I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3388.
18. Sharma, G. V. M.; Reddy, Ch. G.; Krishna, P. R. J. Org. Chem.
2003, 68, 4574.
2. (a) Fukase, K.; Hashida, M.; Kusumoto, S. Tetrahedron Lett.
1991, 32, 3557. (b) Boyer, B.; Keramane, E.-M.; Roque, J.-P.;
19. Creary, X.; Mehrsheikh-Mohammadi, M. E.; McDonald, S.
J. Org. Chem. 1987, 52, 3254.